The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab ...The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.展开更多
As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient...As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.展开更多
Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel ...Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.展开更多
基金by the National Natural Science Foundation of China(Nos.81872809,82073786)the Beijing Natural Science Foundation(L212013).
文摘The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.
基金Natural Science Foundation of Beijing Municipality(L212013)AI+Health Collaborative Innovation Cultivation Project(Z211100003521002)National Natural Science Foundation of China(82073786,81872809,U20A20412,81821004).
文摘As the fourth most important cancer management strategy except surgery, chemotherapy and radiotherapy, cancer immunotherapy has been confirmed to elicitdurable antitumor effects in the clinic by leveraging thepatient’s own immune system to eradicate the cancer cells.However, the limited population of patients who benefitfrom the current immunotherapies and the immune relatedadverse events hinder its development. The immunosuppressive microenvironment is the main cause of the failure,which leads to cancer immune evasion and immunity cycleblockade. Encouragingly, nanotechnology has been engineered to enhance the efficacy and reduce off-target toxicityof their therapeutic cargos by spatiotemporally controllingthe biodistribution and release kinetics. Among them, lipid-based nanoparticles are the first nanomedicines to makeclinical translation, which are now established platforms fordiverse areas. In this perspective, we discuss the availablelipid-based nanoparticles in research and market here, thendescribe their application in cancer immunotherapy, withspecial emphasis on the T cells-activated and macrophagestargeted delivery system. Through perpetuating each step ofcancer immunity cycle, lipid-based nanoparticles can reduceimmunosuppression and promote drug delivery to triggerrobust antitumor response.
基金supported by National Key Research and Development Program (2022YFA1206100, China)Natural Science Foundation of Beijing Municipality (L212013, China)+1 种基金AI+Health Collaborative Innovation Cultivation Project (Z211100003521002,China)National Natural Science Foundation of China(82073786, 81872809, U20A20412, 81821004)
文摘Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.
